Abstract
An efficient immune response requires a selective and strong interaction of T cells with endothelium or target cells. These interactions are strengthened by the rapid induction of beta2-integrin-mediated adhesion upon chemokine receptor or T-cell receptor (TCR) stimulation, respectively. We and others have shown that an increase in G-alpha-s-protein coupled receptor (GalphasPCR) signaling, such as via beta2-adrenergic receptors counteracts chemokine-induced beta2-integrin activation and promotes de-adhesion and mobilization of effector CD8+ T cells from the marginal pool into the circulation. We asked whether GalphasPCR agonists also inhibit integrin activation induced by TCR stimulation of human antigen-specific T cells. Using soluble multimeric ICAM1-Fc-F(ab)2 fluorescent complexes, we developed a flow cytometry assay to identify integrin activation on virus-specific CD8+ T cells following short-term stimulation and staining with cytomegalovirus, Epstein–Barr virus, or influenza virus peptide-major histocompatibility complex class I HLA-multimers. From the GalphasPCR agonists used, epinephrine, norepinephrine, prostaglandins E2/D2 and adenosine strongly down-modulated the beta2-integrin activation on all virus-specific T cells and subsets of different stages of activation, while dopamine, serotonin and histamine had no effects. This active down-modulation of integrin activation through GalphasPCR signaling might be an essential mechanism by which the immune response is suppressed in a variety of pathologies characterized by increased levels of catecholamines (e.g., sleep deprivation), prostaglandins (e.g., tumor growth), or adenosine (e.g., hypoxia).
Published Version
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